The IRONy in Athletic Performance

ron is an essential micronutrient for athletes, intricately linked to their performance, by regulating cellular respiration and metabolism. Impaired iron levels in the body can signi cantly hinder athletic performance. The increased demand for iron due to exercise, coupled with potential dietary iron insuf ciencies, particularly among endurance athletes, ampli es the risk of iron de - ciency. Moreover, prolonged exercise can impact iron absorption, utilization, storage, and overall iron concentrations in an athlete. On the contrary, iron overload may initially lead to enhanced performance; however, chronic excess iron intake or underlying genetic conditions can lead to detri- mental health consequences and may negatively impact athletic performance. Excess iron induces oxidative damage, not only compromising muscle function and recovery, but also affecting various tissues and organs in the body. This narrative review delineates the complex relationship between exercise and iron metabolism, and its profound effects on athletic performance. The article also provides guidance on managing iron intake through dietary adjustments, oral iron supplementation for performance enhancement in cases of de ciency, and strategies for addressing iron overload in athletes. Current research is focused on augmenting iron absorption by standardizing the route of administration while minimizing side effects. Additionally, there is ongoing work to identify inhibitors and activators that affect iron absorption, aiming to optimize the body's iron levels from

adjustments, oral iron supplementation for performance enhancement in cases of de ciency, and strategies for addressing iron overload in athletes. Current research is focused on augmenting iron absorption by standardizing the route of administration while minimizing side effects. Additionally, there is ongoing work to identify inhibitors and activators that affect iron absorption, aiming to optimize the body's iron levels from dietary sources, supplements, and chelators. In summary, by re ning the athletic diet, considering the timing and dosage of iron supplements for de ciency, and implementing chelation therapies for iron overload, we can effectively enhance athletic performance and overall well-being. Keywords:iron; exercise; athletes; iron de ciency; iron overload; diet; treatment; chelation 1. Introduction Iron, an essential mineral trace element (MTE), plays a pivotal role in energy metabolism, oxygen transport, and acid–base balance. Many metabolic enzymes are iron-dependent, including citric acid cycle enzymes aconitase and succinate dehydrogenase [1]. Iron is also indispensable for the electron transport chain governing adenosine triphosphate (ATP) production, as well as in gene regulation, cellular growth, and differentiation [2]. A profound understanding of the intricate mechanisms of iron homeostasis, storage, and regulation in the body is crucial to decipher its role in athletic performance. Iron is a functional component of proteins involved in oxygen delivery (hemoglobin) and storage (myoglobin) [2]. Hemoglobin (Hb) is an iron-dependent protein that directly regulates the level of physical performance [1]. The levels of iron in hemoglobin and other iron-containing proteins within the body are signi cantly in uenced by free iron levels from dietary intake and excretion patterns. Hepcidin, a peptide encoded by the HAMPgene, is one of the primary regulators of iron homeostasis in the body [3]. Hepcidin regulates iron levels by inhibiting ferroportin, a major transporter protein responsible for the transfer of dietary iron from the gastrointestinal tract into the blood [4]. Iron regulatory protein ferritin serves as an intracellular iron storage protein, while transferrin is a blood Nutrients2023,15, 4945.

transfer of dietary iron from the gastrointestinal tract into the blood [4]. Iron regulatory protein ferritin serves as an intracellular iron storage protein, while transferrin is a blood Nutrients2023,15, 4945.

Nutrients2023,15, 4945 2 of 18 glycoprotein that binds to iron and mediates its transport to different parts of the body. Previous reports indicate that most individuals maintain normal levels of iron and iron- dependent proteins; however, athletes often have higher requirements. As an example, conventional ferritin levels are around 30 mcg/l, yet athletes, especially those engaged in high-altitude training where oxygen content in the air is lower, should have levels closer to 50 mcg/l [5]. Recent research has underscored the reciprocal relationship between iron and exercise performance, indicating that iron can impact athletic performance, and exercise in turn can affect iron levels [6]. Of particular interest is the observation that exercise can lead to a condition known as iron de ciency non-anemia (IDNA). This phenomenon is paradoxical as IDNA can also compromise athletic performance [7]. Standard hemoglobin levels are 14 g/dL for men and 12 g/dL for women [1]. In a healthy individual, transferrin has an iron saturation range of 20–50%. On the contrary, transferrin saturation less than 20% indicates iron de ciency and more than 45% sug- gests iron overload. Normal serum ferritin values are, generally, 30–300 ng/L for men, and30–200 ng/Lfor menstruating women. IDNA is characterized by low ferritin levels (<30 ng/mL in the absence of an in ammatory condition and <100 ng/mL in the presence of in ammation) and low transferrin saturation (<20%) with normal hemoglobin levels (13.5–17.5 g/dL for men and 12–15 g/dL for menstruating women). On the other hand, iron de ciency anemia (IDA) is de ned by low serum ferritin (<30 ng/mL without in- ammation and <100 ng/mL with in ammation) and low transferrin saturation (<20%) in addition to low Hb levels (<13.5 g/dL for men and <12 g/dL for women) [8]. Conversely, conditions of iron overload such as hereditary hemochromatosis (HH) can also hinder athletic performance [9]. HH is a condition in which iron absorption from the gut is in- creased due to mutation in any of the iron regulatory proteins. In cases of acute iron toxicity, serum iron levels can reach moderate overload between 350 and 500 micrograms/dL, with levels above 500

of iron overload such as hereditary hemochromatosis (HH) can also hinder athletic performance [9]. HH is a condition in which iron absorption from the gut is in- creased due to mutation in any of the iron regulatory proteins. In cases of acute iron toxicity, serum iron levels can reach moderate overload between 350 and 500 micrograms/dL, with levels above 500 micrograms/dL considered severely toxic. Iron overload is characterized by high serum ferritin levels (>300 ng/mL in men and >200 ng/mL in premenopausal women), which may be non-speci c however, as in ammation, infection, or liver disease can also increase serum ferritin levels. Elevated transferrin saturation (>45%) can assist in further clinical diagnosis. Hence, HH is often associated with elevated serum ferritin and transferrin saturation [10,11]. Studies on the impact of HH on athletic performance are ambiguous. Some studies suggest that athletes with iron levels below the threshold of toxicity may exhibit enhanced athletic performance [12], while others indicate a reduction in athletic capabilities [9,13]. Nonetheless, it is well established that untreated HH can lead to organ damage, including the heart, skeletal muscles, and liver [8,14–16]. Furthermore, excess iron can induce zinc de ciency, which can further limit exercise performance as zinc also plays a vital role in various biological processes in the body [1]. Built upon the literature evidence, this narrative review aims to provide a comprehen- sive understanding of how disturbances in iron homeostasis can affect athletic performance. This includes iron de ciency, a well-documented issue among athletes, and iron overload, which has received less attention in the context of athletic performance. Given that athletes, both professional and amateur, are often targeted by the nutritional supplement industry with the assurance of improved performance, it is crucial to investigate the relative advan- tages of iron supplementation, and simultaneously, the risks associated with iron overload. Additionally, this review seeks to explore the treatment options for both iron de ciency and iron overload including the optimal scheduling of oral iron therapy, dietary factors that may enhance or hinder iron absorption, and therapies used to manage iron overload and toxicity. The goal of

relative advan- tages of iron supplementation, and simultaneously, the risks associated with iron overload. Additionally, this review seeks to explore the treatment options for both iron de ciency and iron overload including the optimal scheduling of oral iron therapy, dietary factors that may enhance or hinder iron absorption, and therapies used to manage iron overload and toxicity. The goal of this review is to provide insights into promoting holistic well-being in athletes to achieve their optimal performance. 2. Methodology A literature search was conducted using the online electronic databases PubMed and Science Direct by searching the keywords `iron', `athlete', `iron de ciency', `iron

Nutrients2023,15, 4945 3 of 18 overload', `exercise', and `physical activity'. This search included human studies and animal experiments. Randomized controlled trials (RCTs), experimental studies, and reviews were included. Articles within the last 15 years were prioritized; however, earlier articles were also included to provide relevant background information. In our screening, we excluded duplicate articles, articles not in English, and articles with no full text available. We excluded articles that were not relevant to answering our research questions (like RCTs on humans not correlating athletic performance and iron status, RCTs on athletes with other conditions that in uenced iron status, and RCTs on humans including participants who were non-athletes). Information from these articles was synthesized together to create a narrative review of the literature. The authors have no nancial or non- nancial con icts of interest that in uenced the selection of research articles, or the outcomes and interpretations in this review. 3. Exercise Leads to Iron De ciency Exercise, particularly high-intensity and endurance training, can result in a substantial depletion of the body's iron stores with reductions of up to 70% observed when compared to the general population. Athletes undergoing intense training frequently encounter an elevated risk of iron de ciency with or without anemia. This condition is often linked to a combination of factors, which paradoxically can also negatively impact athletic perfor- mance [7,17]. The mechanisms underlying this phenomenon are diverse, including poor dietary choices, increased iron requirements, elevated iron loss, in ammation, foot strike hemolysis, thermochemolytic sweat loss, exercise-induced ischemia leading to gastroin- testinal iron loss, hematuria, and decreased iron absorption due to exercise-induced surges in hepcidin mediated by interleukin 6 (IL-6) [5,7,17]. It has been found that sweat may contribute up to 22.5 g of iron lost per liter of sweat [18]. Runners are especially vulnerable to hematuria, due to running-induced trauma in the posterior wall of the bladder [19]. Notably, IDNA is more prevalent in female athletes, affecting approximately 15–35% of female athletes compared to 5–11% of male athletes [20]. Hormones also play a signi cant role in the etiology of IDNA in athletes. Large training

per liter of sweat [18]. Runners are especially vulnerable to hematuria, due to running-induced trauma in the posterior wall of the bladder [19]. Notably, IDNA is more prevalent in female athletes, affecting approximately 15–35% of female athletes compared to 5–11% of male athletes [20]. Hormones also play a signi cant role in the etiology of IDNA in athletes. Large training loads can suppress gonadotropin- releasing hormone (GnRH), along with a decrease in luteinizing hormone (LH) and follicle- stimulating hormone (FSH), which in turn leads to decreased estrogen (E1) levels in women. Additionally, estradiol (E2) supplementation has been found to downregulate hepcidin production. Consequently, lower estrogen may correlate with higher hepcidin levels, in turn, impairing iron absorption in the gastrointestinal tract. Furthermore, extreme acute endurance exercises, such as Ironman competitions, can reduce testosterone levels, which, in turn, suppress hepcidin, further in uencing iron levels [20]. In some cases, the hematological conditions observed in athletes may differ slightly from IDNA and present symptoms similar to anemia. As an adaptation to regular aerobic exercise, plasma volume can increase markedly while erythrocyte volume increases mildly, leading to lower Hb levels due to dilution, manifesting a condition known as pseudo- anemia, or sports anemia [21]. Sports anemia is characterized by increased erythrocyte destruction, impaired iron absorption, and gastrointestinal (GI) blood loss [1]. Possible mechanisms for the development of sports anemia include GI tract malfunction due to an increase in sympathetic tone secondary to intense exercise or stress-induced mechanical destruction of hemoglobin [22]. Other adaptations to training include decreased bone marrow iron stores and increased iron absorption in elite distance runners. However, these low iron levels may be transient, as one study revealed that the initial drop in iron, hemoglobin, and hematocrit levels in female cross-country runners is typically restored to normal over time [1]. Recent research suggests that the type of training an athlete engages in in uences the type and severity of blood-related complications. For example, one study found that endurance athletes tend to have lower hemoglobin and hematocrit levels compared to strength and mixed-trained athletes, potentially due to exercise-induced plasma-volume expansion [23]. Runners

runners is typically restored to normal over time [1]. Recent research suggests that the type of training an athlete engages in in uences the type and severity of blood-related complications. For example, one study found that endurance athletes tend to have lower hemoglobin and hematocrit levels compared to strength and mixed-trained athletes, potentially due to exercise-induced plasma-volume expansion [23]. Runners often exhibit lower haptoglobin levels, which may be attributed to

Nutrients2023,15, 4945 4 of 18 the trauma involved in running, triggering red blood cell destruction. Decreased ferritin levels have been observed in all athletes, with the most pronounced reductions seen in runners [23]. Furthermore, intense training can result in the absorption of iron without adequate binding to transferrin, leading to the release of free iron, which can catalyze reactions producing harmful free radicals. This condition, known as overtraining syndrome, is explored less than IDNA, but can potentially be more dangerous [2]. 4. Iron De ciency Impairs Athletic Performance The relationship between iron status and physical activity is complex and bidirectional, as both in uence each other. For instance, research involving iron-de cient rowing athletes demonstrated that lower ferritin stores were linked to slower rowing ergometer time trial performance [20]. Similarly, experiments conducted with animal models that were fed a low iron diet (LID) revealed lower maximum oxygen uptake and increased muscle fatigue. This was corroborated by a 55% reduction in the respiratory capacity of muscle homogenates in the low-iron group [24]. Several mechanisms may account for this decline in athletic performance in iron- de cient individuals. In the aforementioned mice study, low iron diet (LID) groups ex- hibited lower levels of hemoglobin, cytochrome c, cytochrome oxidase, and mitochon- drial glycerol-3-phosphate dehydrogenase activity, potentially leading to impaired cellular respiration and metabolism. Additionally, reduced oxygen availability in iron-de cient individuals may necessitate greater reliance on anaerobic metabolism, resulting in elevated lactate concentration, lower blood pH, and depletion of muscle glycogen. IDNA also leads to decreased mitochondria, muscle activities of myoglobin, succinate dehydrogenase, and cytochrome c, reinforcing the connection between iron de ciency and reduced exercise capacity [24]. Notably, another study utilizing mice models revealed that iron de ciency impaired overall growth, a condition that was ameliorated upon iron repletion [25]. Hb concentrations were signi cantly lower in iron-de cient groups, with a notable redis- tribution of hemoglobin to the brain during exercise, implying reduced availability in muscles. This group also exhibited reduced glycogen levels, further exacerbating the impact of iron de ciency on physical performance [25]. Since iron is needed for oxygen

condition that was ameliorated upon iron repletion [25]. Hb concentrations were signi cantly lower in iron-de cient groups, with a notable redis- tribution of hemoglobin to the brain during exercise, implying reduced availability in muscles. This group also exhibited reduced glycogen levels, further exacerbating the impact of iron de ciency on physical performance [25]. Since iron is needed for oxygen transport via hemoglobin and serves as a cofactor for several enzymes involved in the aerobic metabolism pathway, these underlying biochemical mechanisms cause low iron to hinder optimal athletic performance [26]. The recommended dietary intake of iron is 8 mg/day for males and 18 mg/day for premenopausal females. However, these recommendations do not consider the augmented iron demands attributable to exercise. Therefore, it is imperative to recognize that athletes, particularly endurance athletes like runners, may need 70% more iron intake per day [27]. Female athletes often need additional iron supplementation due to menstrual blood loss [28]. Moreover, IDNA is at least twice as common as iron de ciency anemia (IDA), yet it often goes unnoticed by clinicians [29]. IDA is well reported to cause symptoms such as fatigue, muscle weakness, and compromised cognitive function [30], all of which can contribute to poor athletic performance. In many instances, early detection of IDNA is important, especially in high-risk patient groups. In a study of 121 recreationally active adults, IDNA was prevalent in 29% of females, compared to 4% in males. Using the transferrin receptor– ferritin index, these numbers increased to 36% for females and 6% for males [31]. In another study of 14 female runners, 50% were found to be iron de cient at baseline, with over 70% de cient after a training regimen [32]. Various factors elevate the risk of iron de ciency, including vegan or vegetarian diets, frequent blood donation, adolescence, eating disorders such as anorexia nervosa or bulimia nervosa, heavy menstruation, gastrointestinal disorders or surgeries, and intensive athletic training [5]. IDNA remains a diagnostic challenge, lacking well-de ned criteria. Suspicion of IDNA should arise when a patient exhibits symptoms of iron de ciency without anemia, combined with low serum ferritin

ciency, including vegan or vegetarian diets, frequent blood donation, adolescence, eating disorders such as anorexia nervosa or bulimia nervosa, heavy menstruation, gastrointestinal disorders or surgeries, and intensive athletic training [5]. IDNA remains a diagnostic challenge, lacking well-de ned criteria. Suspicion of IDNA should arise when a patient exhibits symptoms of iron de ciency without anemia, combined with low serum ferritin levels [33]. A thorough medical history is also crucial, considering factors such as blood donations, accidents resulting in signi cant blood loss, or surgery, as

This review explores the relationship between iron metabolism and athletic performance.